Advances in translational research are paramount for the progress of clinical medicine, with patients having complex, and seemingly insurmountable problems providing a constant stimulus and direction for new avenues of exploration. A major hurdle in the implementation of such a program is the traditional lack of interaction between physicians and scientists. Recognizing this limitation, the head and neck oncology translational research program is organized as an integral part of the Division of Head and Neck Surgery and Oncology, and the Department of Otolaryngology. The primary mission of the program is to facilitate the translation of developments in basic science research into clinical practice. It is anticipated that this approach will have a positive impact on the prevention, diagnosis, treatment and ultimately, the cure and quality of life, of patients suffering from head and neck cancer.

The major focus of our research program is on the immunotherapy of head and neck cancer. The New York University School of Medicine has a long and distinguished history of excellence in immunology research, which includes two Nobel laureates in this field. This distinguished history currently continues with a very active program in tumor vaccines in Malignant Melanoma and Prostate cancer. Coupled with excellent infrastructure for both basic science and clinical research, and our commitment to collaborative translational research approaches, we are confident that we can achieve our goals.

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Milestones

• Appointments of key personnel: Mark D. DeLacure MD- October 1998,
  M. Abraham Kuriakose MD- January 1999, Fang-An Chen Ph.D.- July 1999,
  Renato J. Giacchi MD, July 1999, Zhi-Hua Tong BS- February 2000.
• Head and neck immunotherapy protocol approved by the NYU Institutional Research Review Board, February 1999.
• Rusk Research Building Laboratory # 8-18 assigned for the Head and Neck Oncology Research Program on 29, March 1999.
• Animal care space was allocated within the Medical Science Building Animal Facility for Head and Neck Cancer research projects, in March 1999.
• American Head and Neck Society Young Investigator Career Development Award, April 1999.
• Clinical Investigator Pilot Research Award, NYU School of Medicine, June 1999.
• Established collaboration with ImClone Systems Incorporated for anti-EGFr antibody clinical trial, June 1999.First successful head and neck tumor engraftment in SCID mice at NYU, August 1999.
• Major laboratory equipment procurement and installation completed in November 1999.
• Secured material transfer agreement with the Genetics Institute, Boston for Cytokine-IL-12, and with Immunex, Washington, for anti-41BB monoclonal antibody and GM-CSF, January 2000.
• Obtained collaboration agreement with Atrix Laboratories Inc. to develop biodegradable polylactic acid-mediated cytokine delivery system, January 2000.
  
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Personnel

The head and neck oncology research program was initiated under the leadership of Mark D. DeLacure MD, in October 1998. The team consists of a surgeon-educator, surgeon-scientist, scientist and a laboratory technician, with a proven track record of collaborative research.

Mark D. DeLacure MD,is a native Floridian who obtained his B.S., Magna Cum Laude, in Biochemistry and Pharmacology from the University of Florida in Gainesville in 1982. He also completed his M.D., Cum Laud, at the University of Florida in 1986. From there he left for northern California where he completed preliminary General Surgical residency training at the Stanford University Medical Center in Palo Alto, California. He then completed a Residency in Otolaryngology-Head and Neck Surgery at Yale University Medical Center in New Haven, Connecticut. Dr. DeLacure then served as Fellow in Head and Neck Surgery at the Memorial Sloan-Kettering Cancer Center in New York City. He then left again for California, completing a residency in Plastic and Reconstructive Surgery at University of California at Los Angels (UCLA). Dr. DeLacure is Board-Certified by both the American Board of Otolaryngology and the American Board of Plastic Surgery. He joined the staff of the Department of Head and Neck Surgery and Oncology at the Roswell Park Cancer Institute in 1994 and served as Chairman of the Department of Head and Neck Surgery and Oncology and Section of Plastic and Reconstructive Surgery from 1966-1998. He was recruited to NYU in 1998 as Director of the Division of Head and Neck Surgery and Oncology and Associate Professor in the Institute of Reconstructive Plastic Surgery.

M. Abraham Kuriakose MD, DDS,is the team’s Surgeon-Scientist. Dr. Kuriakose obtained his B.Sc. in Biology from the University of Kerala, in 1979 with honors and graduated in Dentistry (BDS) from theUniversity of Mysore, India in 1983 with distinction and honors. He then moved to the United Kingdom, where he completed MD from the University of Bristol in 1992. He completed General Surgery Residency in Bristol. He then trained in Oral and Maxillofacial Surgery at the Welsh Regional Plastic and Maxillofacial Surgery Center, Chepstow, and Craniofacial Surgery at the University of Newcastle. Further to that he underwent advanced fellowship training in Head and Neck Surgery and Oncology at the Roswell Park Cancer Institute in Buffalo. Dr Kuriakose is a Fellow of the Royal College of Surgeons of England, Edinburgh and Ireland. He is also certified by the United Kingdom Intercollegiate Board of Examinations in Maxillofacial Surgery. He was recruited to NYU in January 1999, where he is an Assistant Professor of Otolaryngology and Director of the Head and Neck Oncology Translational Research Program.

Fang-An Chen MD, PhD,is a Research Associate Professor in the Head and Neck Oncology Translational Research Program. Dr. Chen graduated in Medicine from the School for Traditional Chinese Medicine, Shanghai in 1968 and obtained a Ph.D. in Molecular Immunology from the State University of New York at Buffalo in 1990. He joined the Department of Molecular Immunology at the Roswell Park Cancer Institute, Buffalo as a Research Fellow in 1983 and later became a faculty of the Department. He has over ten years post-doctoral experience in Molecular Immunology and was involved in pioneering work on Cytokine immunotherapy at the Roswell Park Cancer Institute.

Zhi-Hua Tong BS,graduated from the Shanghai School of Technology in 1968 and underwent advanced training in bioscience research at the National Chemistry and Technology Institute of China. She joined the Department of Molecular Immunology, at the Roswell Park Cancer Institute in Buffalo as Research Technician in 1989. She has extensive experience in molecular biology, immunology research and SCID mice experiments. Hua will be joining the Head and Neck Oncology Research Program in February 2000 as a Laboratory Technical Assistant.

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Laboratory Facilities

Laboratory space was allocated for Head and Neck Oncology Research in the Rusk Research Building (8-18) in March 1999. Efforts for the procurement of equipments were commenced immediately. The installation and calibration of equipment was completed in November 1999. The following is a brief description of the major equipment procured for the head and neck laboratory.

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Research Projects in Process

The immediate focus of the head and neck oncology research program is to develop an effective immunotherapeutic strategy for head and neck cancer, with a view to improve the cure rate and quality of life of patients suffering from these tumors. In order to achieve these goals several research projects are initiated under this program, with particular emphasis on cutting-edge translational research.

• H 8414-01: Phase IB/IIA Pharmacokinetics/Pharmacodynamics Study of Anti-Epidermal Growth Factor Receptor (EGFr) Antibody C221 in patients with newly diagnosed head and neck cancer.
  Anti-Epidermal Growth Factor Receptor (EGFr) Antibody has been shown to suppress the growth of head and neck and lung tumors in pre-clinical animal experiments and in early clinical studies. In this clinical trial, we will be determine the optimal dose regimen of this antibody and the toxicity profile of the antibody in patients with head and neck cancer.
  
  
• H 8428-01: Lymphoscintigraphy-Assisted Molecular Staging of Head and Neck Cancer
  Advances in molecular biology afford us the ability to determine the molecular markers of head and neck squamous cell carcinoma (HNSCC) for the early detection of cervical nodal metastasis. The inability to accurately localize the high-risk node on which to focus investigation has hampered the translation of this finding to clinical practice. This project attempts to investigate the effectiveness of lymphoscintigraphy-assisted localization of high-risk sentinel lymph nodes and applies molecular biology techniques to identify micro-and sub-microscopic metastases of HNSCC.
  
  
• H 8423-01: Head and Neck Cancer Immunotherapy with Biodegradable Microspheres
  Cytokine gene therapy is now well-established in in vitro and pre-clinical animal research studies as a viable anti-tumor strategy. Though it may circumvent the toxicity observed with systemic cytokine therapy, the implementation of this strategy in clinical practice is hampered by several technical limitations. While labor-intensive ex-vivo transfection is restricted by the difficulty of maintaining and expanding tumor cells in culture, the in vivo gene manipulation attempts have serious drawbacks of low transfection efficiency and the possibility of a misdirected immune response. This project attempts to overcome these limitations with the use of biodegradable microspheres for the local and sustained delivery of cytokines and other immunostimulatory agents into the tumor milieu. In vitro and in vivo studies have already demonstrated the clinical feasibility of this strategy.
  
  
• IACUC 4282-01: SCID/hu Chimeric Tumor Model of Head and Neck Squamous Cell Carcinoma
  Distinct from chemotherapy or radiotherapy, the investigation of the immunotherapy of human cancer requires the presence of human immuno-competent cells. The lack of an animal model, which incorporates human immuno-competent cells, has prevented optimal pre-clinical characterization of immunotherapeutic strategies. The objective of this project is to develop a chimeric human tumor/lymphocytes-SCID mouse model [huT/L-SCID] involving the simultaneous engraftment of human tumor and immuno-competent lymphocytes. Preliminary results suggest that it is possible to co-engraft head and neck squamous cell carcinoma and the same patient’s lymphocytes in SCID mice. The engrafted lymphocytes are responsive to cytokines and other immunomodulatory regimens. This animal model, for the first time, allows scientists to evaluate and characterize the effectiveness of human cytokines in activating human lymphocytes against the same patient’s head and neck cancer cells.
  
  
• H 8539-01: Cancer Susceptibility Genes and Oral Cancer Risk
  The objective of this research project is to examine genetic polymorphic markers of enzymes involved in tobacco carcinogen metabolism in a case-control study of oral cavity cancer cases versus matched non-cancer controls in order to assess individual susceptibility to oral cancer. Many tobacco carcinogens are metabolically activated to electrophilic derivatives by several groups of cellular enzymes. The principal phase I enzymes responsible for oxidative conversion are the cytochrome P450 enzymes such as CYP1A2 and CYP1B1 for polycyclic aromatic hydrocarbons (PAHs) and CYP1A2 and CYP2E1, for nitrosaminase. Metabolic deactivation of P450-activated pro-carcinogens can also occur, primarily through the activity of transferase enzymes such as N-acetyltransferases, glutathione S-transferases (GSTs), and the UDP-glucuronosyltransferases. Therefore, the carcinogenic activity of tobacco carcinogens can often depend on the cellular composition of P450s and transferases, and this composition may be a critical determinant of individual risk to tobacco carcinogen-induced damage. Extensive epidemiologic data have established that tobacco use is the major risk factor for oral squamous cell carcinoma. It is the goal of this research project to utilize polymorphic markers of these xenobiotic-metabolizing enzymes to assess individual’s susceptibility to Oral cancer in a case-control molecular epidemiologic study.
  
  
• H 84339-02: Biological Prognostic Markers of Nasopharyngeal Carcinoma
  Nasopharyngeal cancer, with high prevalence among the Asian community, has a significant risk for systemic metastasis. In this clinical study the investigators are evaluating the usefulness of biological markers(beta-Catenin, E-Cadherin, Ki66, MIB, neoangiogenicity) to identify patients who are at risk of distant metastasis and treatment failure. It is anticipated that information like this will help to tailor treatment based on the patients’ risk profiles.
  
  
• H 8720-01: Patterns of Facial Growth following Skull Base Irradiation
  A number of children with tumors located at the base of the skull are effectively treated by radiation therapy. With improved cure rates, we are observing long-term side effects of these treatments. One such problem is the effect on facial skeletal growth. In this study we are investigating the patterns of craniomaxillofacial growth in children who have had radiation therapy for skull base tumors.
  
  
• Use of Biodegradable Plating Systems for Osteosynthesis in Reconstructive Head and Neck Oncologic Surgery.
  Resorbable plating systems for the craniofacial skeletons have been developed originally for pediatric craniofacial applications where restriction of continued craniofacial growth and transcranial migration of osteosynthesis plates under growth-related traction forces are of particular concern. Clinical experience in a variety of contexts has confirmed their advantages. Such systems offer potential advantages in application to oncologic reconstruction, namely the progressive transfer of biomechanical stress to grafts, flaps and osteotomies (a favorable physiologic phenomenon), the absence of interference with diagnostic imaging studies via postoperative imaging artifact, relative radiotransparency, and lack of interference with radiation dosimetry as compared to their metallic counterparts. This study involves investigation of the effectiveness of biologically resorbable plating system in reconstructive head and neck oncologic surgery.
  
  
• Distraction Osteogenesis for the Reconstruction of Segmental Mandibular Defects
  Distraction osteogenesis is an established technique for the lengthening of long bones and the correction of selected craniofacial deformities. Regenerate osteoid bone matrix formed during the distraction phase is malleable and can recreate the three-dimensional form of native bones. Animal experiments and early clinical studies have confirmed that distraction osteogenesis can be used for the reconstruction of segmental bony defects. This research project explores the clinical application of this
  principle in the reconstruction of mandibular continuity defects.
  
  
• Randomized Phase III trial to Compare Radiation Therapy Alone with Radiation therapy and Concomitant anti-EGFr Antibody for Locally-advanced Squamous Cell Carcinomas of the Head and Neck.
  Epidermal Growth Factor receptor (EGFr) is a commonly expressed transmemembrane glycoprotein that is a member of the tyrosine kinase growth factor receptor family. This receptor and its growth factor is encoded by proto-oncogene c-erb-B. It has been shown that activation of the EGFr receptor by EGF or Transforming Growth Factor-alpha causes cellular proliferation. Blocking this receptor has been shown to inhibit the proliferation. C225, a humanized monoclonal antibody, has been shown to effectively block EGFr. Head and neck squamous cell carcinomas have overexpression of EGFr. Early clinical experience has suggested that the blocking of this receptor by the monoclonal antibody may be an effective anti-tumor strategy. In this phase III clinical trial, the investigators will evaluate the anti-EGFr antibody’s effectiveness in combination with radiation therapy compared to radiation therapy alone in the treatment of advanced head and neck cancer.
  
  
• Intra-lesional Delivery of Cisplatin with Atrigel in Head and Neck Squamous Cell Carcinoma.
  In this animal research, the investigators will evaluate the effectiveness of the delivery of Cisplatin, a well-established chemotherapeutic agent in head and neck cancer, using Atrigel, a biodegradable polymer with phase transformation properties. Developing such novel strategies of drug delivery may potentially minimize the systemic toxicity of such chemotherapeutic agents, traditionally administered intravenously.

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